Insulin resistance contributes to the pathogenesis of several disease states including obesity and type 2 diabetes mellitus . We have investigated the nature of the genetic factors that predipose to the development of insulin resistance. Previously, we have identified mutations in the insulin receptor gene in patients with several genetic syndromes associated with insulin resistance. More recently, several variant sequences have been identified in the gene encoding insulin receptor substrate-1 (IRS-1); these variant sequences have been reported to be more prevalent among patients with noninsulin-dependent diabetes mellitus. To investigate the signficance of these amino acid substitutions, we have expressed several of the mutant proteins by transfection in mammalian cells. However, under our experimental conditions, none of the amino acid substitutions (including the most common variant, Gly972Arg-IRS-1) caused a functional defect in recombinant IRS-1. These negative observations do not support the hypothesis that polymorphisms in the amino acid sequence of IRS-1 contribute to the cause of insulin resistance in patients with type 2 diabetes. We are also carrying out clinical investigation of patients with various forms of lipoatrophy, most of whom also have insulin resistant diabetes. We have initiated therapy with troglitazone in order to determine whether this agent will improve metabolic control in these patients with a paucity of adipose tissue. In the course of follow-up, we will also determine whether troglitazone leads to an increase in body fat. Finally, we are establishing cell lines as a source of DNA from these patients in order to identify the genes that cause lipoatrophy in patients with genetic forms of the syndrom (especially Dunnigan's syndrome, a form of partial lipoatrophy transmitted with an autosomal dominant from of inheritance).